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Norharman, an indoleamine-derived beta-carboline, but not Trp-P-2, a gamma-carboline, induces apoptotic cell death in human neuroblastoma SH-SY5Y cells.

Authors
  • Uezono, T
  • Maruyama, W
  • Matsubara, K
  • Naoi, M
  • Shimizu, K
  • Saito, O
  • Ogawa, K
  • Mizukami, H
  • Hayase, N
  • Shiono, H
Type
Published Article
Journal
Journal of neural transmission (Vienna, Austria : 1996)
Publication Date
Jan 01, 2001
Volume
108
Issue
8-9
Pages
943–953
Identifiers
PMID: 11716147
Source
Medline
License
Unknown

Abstract

Carbolines, azaheterocyclic amines derived from indoleamines, have various biological activities, such as neurotoxicity of beta-carbolines and potent mutagenicity of gamma-carbolines. In this study, structural significance among these carbolines was investigated in relation to the types of cell death, apoptosis and necrosis, using human neuroblastoma SH-SY5Y cells. DNA damage was quantitatively analyzed by a single-cell gel electrophoresis assay. DNA damage was induced by both beta-carbolines, harman and norharman, and gamma-carbolines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-4-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), in a dose dependent manner. Gamma-carbolines were more potent to damage DNA than beta-carbolines. Alkaline lysis of the cells prevented DNA damage induced by beta-carboline, and pre-treatment of the cells with cycloheximide, an inhibitor of protein synthesis, reduced DNA damage caused by norharman. Morphological observation showed condensed and fragmented nuclei typical for apoptosis, in the cells treated with norharman. Thus, DNA damage induced by norharman was proved to be apoptotic. However, harman, which had a methyl substitution at the position 1, might induce necrosis in the cells. On the other hand, gamma-carbolines, Trp-P-1 and Trp-P-2, directly damaged DNA. Thus, the nitrogen atom at the gamma-position and/or an amino group in carboline structure would be required to induce the direct DNA cleavage.

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